This project is directed toward developing effective therapies for the treatment of metastatic thyroid cancers with RAS mutation that have become refractory to radioiodide treatment. It is based on the following ideas: 1)The grovrth of RAS mutant tumors is dependent upon ERK signaling; 2)in these tumors, activated ERK feedback inhibits RAF activity and receptor tyrosine kinase 3)lnhibition of ERK with standard MEK inhibitors relieves these feedbacks and activates RAF and RTK signaling. Activation of RAF attenuates inhibition of ERK signaling and, together with reactivation of receptor tyrosine kinase signaling attenuates the potential therapeutic effects of ERK pathway inhibition. We hypothesize that maximal pharmacologic inhibition of ERK will be obtained with drugs that prevent or are refractory to feedback reactivation of RAF and that they will have enhanced antitumor activity. We have developed two such drugs~an allosteric MEK inhibitor that causes MEK to bind tightly to RAF and inhibit its activity and an ERK inhibitor that causes ERK to be refractory to upstream activity of MEK. We now propose to: Aim 1. Use these drugs, alone or in combination, to develop a regiment that optimally inhibits ERK activation by bypassing relief of RAF feedback and then test the antitumor activity of this regimen. Aim 2.Maximal inhibition of RAF will powerfully reactivate receptor tyrosine kinase signaling and this will decrease its therapeutic effect. In this Aim, we will identify the receptor systems that are reactivated in RAS mutant thyroid cancers when ERK feedback is relieved. Aim 3.We hypothesize that maximal inhibition of ERK signaling in combination with inhibition of reactivated receptor tyrosine kinase signaling will comprise effective therapy for these tumors. This assertion will be tested in this Aim in tissue culture and xenograte models of thyroid carcinoma with mutant RAS. The overall goal of this project is the development of novel effective therapy of thyroid cancer that is based on these principles.